We propose to conduct a genetic epidemiology haplotype association project evaluating polymorphisms[unreadable] of genes in the NER and cell cycle control pathways in a series of NSCLC cases and controls. The ability to[unreadable] identify individuals with the highest risk of developing tobacco-related cancers, most importantly lung cancer,[unreadable] has important public health and clinical implications for screening, early detection, prevention and treatment.[unreadable] In addition to variability in activation and detoxification pathways of mutagenic agents, there is a very strong[unreadable] biologic rationale to also study the variability in the capacity to repair smoking induced DNA damage as[unreadable] another major family of susceptibility biomarkers. The nucleotide excision repair (NER) pathway is important[unreadable] in the repair of chemical carcinogen induced genotoxic damage. The XPD protein is a key member of this[unreadable] pathway and mutations in the XPD gene, including the common A35931C (Lys751Gln) variant allele, result[unreadable] in reduced repair capacity. Furthermore, regulation of the cell cycle control mechanism can influence the[unreadable] potential for increased cell proliferation and the promotion of genetic instability. Cyclin D1 (CCND1) is an[unreadable] essential cell cycle regulatory protein and is involved in the regulation of proliferation and differentiation. Our[unreadable] initial case/control studies have demonstrated a significant association between elevated risk of upper[unreadable] aerodigestive tract cancer among individuals who carried both the CCND1 870A variant allele and XPD Gin[unreadable] allele (OR=7.1, 95%CI 4.0-12.5). We propose to extend these observations to include a pathway haplotype[unreadable] association analysis, focusing on all of the 25 genes involved in the NER pathway and 5 key cell cycle[unreadable] control genes, in order to capture all of the common genetic variation within the selected genes in the two[unreadable] pathways of interest and evaluate how this variation contributes to lung cancer risk. To test the prognostic[unreadable] significance of these haplotypes, we will also perform a prospective study by genotyping the PLuSS and[unreadable] Moffitt Cancer Center High-Risk sub-cohorts. We will also develop a final predictive model by combining the[unreadable] datasets from the case/control and prospective studies in Specific Aims 2 and 3 for purposes of external[unreadable] validation. The NER gene haplotypes may not only predict lung cancer risk, but also drug resistance and[unreadable] survival. It is well known that resistance to platinum-based drugs, a chemotherapeutic regimen often used in[unreadable] the treatment of lung cancer, is associated with up-regulation of NER proteins. In order to further evaluate[unreadable] the haplotype/phenotype relationship, we propose to study the relationship of the NER haplotype with[unreadable] response to platinum-based drug treatment among the lung cancer cases. This haplotype-based approach[unreadable] will provide a great amount of information about genes and pathways and will help to evaluate how genetic[unreadable] variation relates to lung cancer risk. The ability to rapidly screen individuals for risk and prognosis, using[unreadable] non-invasive procedures, has tremendous potential for future clinical application.[unreadable]